The predominant HIV-1 subtype found in US and Western World is clade B, which differs significantly from clade C that exists in sub-Saharan Africa and Asia. Estimates suggest that out of about 46 million people infected with HIV-1, more than 56 % of the infection is with clade C alone and HIV-1C infection is rapidly spreading to other parts of the world. AIDS is often accompanied by neuropathological abnormalities. Cocaine is one of the most widely abused drugs in the U.S. Current understandings of HIV-1 neuropathogenesis or the role of cocaine emanate from B clade from U.S. and Western countries and no information is available on the interactive role of cocaine on neuropathogenesis of C clade. We hypothesize that clade B and C exert differential effects on CNS cells leading to differential neuropathogenesis and cocaine exacerbates these effects and the mechanisms may be mediated by dysregulation of mitogen activated protein (MAP) kinases signal transduction pathways. Accordingly we will study (Aim #1a) for the first time the effects of in vitro infection with clade B and C virus in presence or absence of cocaine on production and gene expression of pro-inflammatory cytokines, (TNF1 &IL-6), chemokines (MCP-1&RANTES), and neurotoxin (IDO) by primary monocytes and CNS cells (astrocytes, neurons, microglial cells), and whether :(Aim #1b) the mechanism of differential dysregulation is mediated by modulation of mitogen activated protein (MAP) kinases signal transduction pathways. Further these in vitro infection studies will be compared, correlated and complemented with ex vivo studies (Aim #2) using monocytes from naive HIV-1B infected subjects who are using and non using cocaine being studied in Miami and cocaine using and non using HIV-1C infected subjects being studied at the collaborating institute in India. The results emanating from these studies may a) help to develop therapeutically useful drugs or agents which could attenuate or prevent the neuropathogenesis associated with clade specific HIV-1 infection and cocaine use and b) design novel strategies to develop preventive and therapeutic global vaccines that can induce cross-clade antiviral immune response against multiclade or recombinant pandemic HIV-1 infection that is currently facing the world including United States where non B subtypes have been recently reported in migrant populations and among our military personals. PUBLIC HEALTH RELEVANCE This application has significant relevance to the purpose of the PA-07-307.This project will study for the first time the interactive role of cocaine on production and gene expression of neuropathogenic molecules in HIV-1B and HIV-C infection by both in vitro and ex vivo model system. Identification of the mechanism of clade specific neuropathogenesis will help to design novel strategies to develop preventive and therapeutic global vaccines in drug using and non-using HIV infected subjects that can induce cross-clade antiviral immune response against multiclade or recombinant pandemic HIV-1 infection that is currently facing the world including United States.